Abstract
Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic andendothelial cells expressed PD-L1.PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3062-3073 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 122 |
| Issue number | 17 |
| DOIs | |
| State | Published - Jan 1 2013 |
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ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology
Cite this
Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. / Saha, Asim; Aoyama, Kazutoshi; Taylor, Patricia A.; Koehn, Brent H.; Veenstra, Rachelle G.; Panoskaltsis-Mortari, Angela; Munn, David H; Murphy, William J.; Azuma, Miyuki; Yagita, Hideo; Fife, Brian T.; Sayegh, Mohammed H.; Najafian, Nader; Socie, Gerard; Ahmed, Rafi; Freeman, Gordon J.; Sharpe, Arlene H.; Blazar, Bruce R.
In: Blood, Vol. 122, No. 17, 01.01.2013, p. 3062-3073.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality
AU - Saha, Asim
AU - Aoyama, Kazutoshi
AU - Taylor, Patricia A.
AU - Koehn, Brent H.
AU - Veenstra, Rachelle G.
AU - Panoskaltsis-Mortari, Angela
AU - Munn, David H
AU - Murphy, William J.
AU - Azuma, Miyuki
AU - Yagita, Hideo
AU - Fife, Brian T.
AU - Sayegh, Mohammed H.
AU - Najafian, Nader
AU - Socie, Gerard
AU - Ahmed, Rafi
AU - Freeman, Gordon J.
AU - Sharpe, Arlene H.
AU - Blazar, Bruce R.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic andendothelial cells expressed PD-L1.PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
AB - Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic andendothelial cells expressed PD-L1.PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
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U2 - 10.1182/blood-2013-05-500801
DO - 10.1182/blood-2013-05-500801
M3 - Article
VL - 122
SP - 3062
EP - 3073
JO - Blood
JF - Blood
SN - 0006-4971
IS - 17
ER -